Investigation on the efficiency of lentinan for injection combining cisplatin on treating malignant pleural effusion based on systematic review and meta-analysis

Background: Malignant pleural effusion (MPE) is a frequently observed complication in advanced malignant tumors. Clinical studies have shown that lentinan for injection (LNT) is beneficial for improving patients’ quality of life and prolonging their survival. The purpose of this meta-analysis is to evaluate the efficacy and safety of LNT combining cisplatin in the treatment of MPE. Methods: Randomized controlled trials (RCTs) of LNT combining cisplatin in the treatment of MPE were searched in 6 literature databases from the establishment time of each database by 2 researchers. According to the inclusion criteria, 2 researchers independently screened studies, assessed the risk of bias and conducted subgroup analyses for different outcome indicators according to the specific characteristics of the included literature. Analyzing the data by Revman software, and evaluating the stability of the results by Stata software. Results: A total of 52 RCTs were included. The results showed that combined use of LNT and cisplatin could improve the treatment effect, and the difference between groups was statistically significant (RR = 1.40, 95%CI: 1.33 ~ 1.46, P < .001). And the combined use of LNT could increase the quality of life (RR = 1.45, 95%CI: 1.35 ~ 1.56, P < .001). The using of LNT could significantly decrease the incidence of gastrointestinal reactions (RR = 0.86, 95%CI: 0.78 ~ 0.94, P < .001). Sensitivity analysis results showed that there were no qualitative changes in the indicator, and suggested the possibility of publication bias. Conclusions: Available evidence suggested the combined use of LNT and cisplatin showed better efficacy in treating MPE without increasing ADR incidence than using cisplatin alone. LNT is an ideal treatment for MPE, which has high clinical application value.


Introduction
Malignant pleural effusions (MPE) are characterized by the accumulation of fluid in the pleural space, resulting from lung cancer or other malignant tumors affecting the pleura, which is a frequently observed complication in advanced-stage malignancies. [1]In the case of MPE, more than 3-quarters of patients suffer from lung cancer or breast cancer, with metastatic adenocarcinoma being the most prevalent subtype in China. [2,3]Patients with MPE are often accompanied by symptoms such as chest tightness, palpitations, fever, shortness of breath, dry cough, and chest pain, which suggest a poor prognosis. [4]Currently, the commonly employed clinical treatment methods for pleural effusion include therapeutic thoracentesis, chemical pleurodesis, indwelling thoracic drainage tube, indwelling thoracic catheter combined with chemical pleurodesis, systemic anti-tumor therapy, etc. [5] Pleural effusion drainage combined with drug pleural perfusion is widely practiced in clinic due to its simplicity, minimal invasiveness, and reduced risk of individual complications.Cisplatin, a chemotherapeutic drug, has proven effective in managing pleural effusion.It can not only control the progression of cancer, but also induce inflammation and occlusion of pleural adhesion to control pleural effusion.However, cisplatin is highly toxic, and patients are prone to adverse reactions such as bone marrow suppression, gastrointestinal reactions, and liver function damage.
In recent years, as an important adjuvant treatment, traditional Chinese medicine has been widely used in clinical practice.[8] Lentinus edodes polysaccharide is an effective active ingredient extracted from the fruiting body of high-quality L edodes.The active ingredient in L edodes is branched β -(1-3) -D-glucan.The main chain of L edodes is composed of β -(1-3) -linked glucose groups.Lentinan injection is an immunomodulator and is used as an adjuvant therapy for malignant tumors.LNT has been extensively studied for its pharmacological effects, and has demonstrated various beneficial properties.It has been found to enhance the immune system, possess anti-tumor, antibacterial, antiviral, and neuroprotective properties.Additionally, LNT exhibits pharmacological activities such as antidepressant, antioxidant and anti-aging. [9,10]everal studies have suggested that LNT can effectively control MPE and reduce the occurrence of adverse drug reactions (ADR), such as gastrointestinal issues and hematological toxicity.It also improves the quality of life and extends the survival period of patients, particularly in older patients who may have difficulties tolerating aggressive chemotherapy.Therefore, considering the adverse effects of existing chemotherapy drugs, and the prominent advantages of lentinan injection in improving immunity, LNT combining cisplatin (DDP) is an effective treatment option for MPE. [11]he current studies on LNT in the treatment of MPE are abundant, but there is a lack of evidence-based researches.This research aims to conduct a systematic review by screening out the studies related to LNT in the treatment of MPE.The research will utilize the method of meta-analysis and computer aided technology to comprehensively analyze and evaluate the collected studies, to clarify the efficacy and safety of LNT in the treatment of MPE, and provide new evidence-based evidence for rational use of drugs in MPE patients.

Methods
The procedure of the current research was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.The PRISMA checklist is shown in Guidelines Checklist.

Search strategy
To retrieve relevant literature, a comprehensive search strategy was carried out using the following databases: China National Knowledge Infrastructure, Wanfang, China Science and Technology Journal Database, Chinese Biomedical Literature Database (Sinomed), PubMed, and Embase databases.The search was conducted from the inception of each database until March 2, 2023, and a combination of MeSH terms and free text was used to identify randomized controlled trials (RCTs) investigating the use of LNT in the treatment of MPE.For example, the search strategy used in PubMed is outlined in Supplemental Digital Content, http://links.lww.com/MD/M580.

Inclusion criteria
2.2.1.Types of studies.Clinical randomized controlled trials that reported the efficacy of LNT combining DDP in the treatment of MPE were required.If the "random" is mentioned in the literature, no matter in which language, publication year, or publication status.

Types of participants.
Participants, regardless of gender, age, race, etc, were all diagnosed according to a large amount of pleural effusion in chest by X-rays and B-ultrasound.The patients or family members accepted an informed consent form.

Types of interventions.
All RCTs conducted pleural effusion drainage and only used DDP as a chemotherapy drug for intrapleural injection.Based on the control group, the trial group only added intrapleural injection of LNT.To reduce the adverse reactions of patients, targeted treatment drugs such as lidocaine, dexamethasone, granisetron, lasix, promethazine, ondansetron (OD), and metoclopramide (MP) were also allowed to be used.The control group and trial group did not use other traditional Chinese medicine (TCM) and adjuvant methods, and the drug dosage and duration were not limited. of gastrointestinal reactions; The incidence of liver function injury; The incidence of renal injury; The incidence of fever; The incidence of chest pain.

Exclusion criteria
If the studies met these conditions were excluded: the studies were not consistent with the efficacy evaluation criteria or the required outcome types were not found; the studies used other TCM treatments in the trial or control groups; the full texts cannot be obtained.For duplicate studies, only those with complete data or the most recent literature were included.

Data extraction and quality assessment
The 2 researchers (YW and HW) independently screened studies by the NoteExpress software, and extracted data.In cases where there were differences in screening or data extraction, it was determined by discussing or seeking the opinion of a third researcher (XZ).After removing duplicate records, the researchers removed obvious incompatible documents by reading literature title and summary.The remaining documents were then read in full, and those that met the inclusion criteria were selected.The collected data was organized using Excel software.The extracted content included the first author name and publishing year, the number of participants in the trial and control groups, the gender and age distribution in both groups, the disease staging, KPS score, survival time, intervention measures, treatment details, outcome data, and so on.
The risk of bias in the studies was assessed using the risk of bias tool 2.0 (RoB2) from Cochrane to randomized clinical trials.RoB2 was also performed in pairs by 2 independent reviewers (KC and HW).If there was disagreement between the 2 evaluators about the risk of bias analyzed, a third reviewer (JW) performed the consensus.The evaluators examined the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results.Thus, the studies were classified into low, some concerns, or high risk of bias.

Data analysis
The data collected from the included studies were analyzed using the Revman software 5.3. [12]For binary variable, the Relative Risk (RR) was selected as the statistical index, while for continuous variables, the mean difference statistics were used.The 95% Confidence Interval (95% CI) was calculated for both types of variables.Heterogeneity testing is performed through Q test and I 2 test.When P > .1 and I 2 < 50%, use a fixed-effect model, otherwise the heterogeneity is excluded, and the random-effect model is used. [13]To evaluate the stability of the results, the analysis was conducted by excluding one study at a time using Stata 14.0 software, [14] which helped determine if the results were robust and not heavily influenced by any single study.Employing subgroup analysis, such as conducting analyses of treatment effects based on different evaluation criteria and analyzing life quality evaluation indicators according to medication dosage, enabled the assessment of differences in intervention effects across different subgroups.This approach enhanced the specificity of clinical guidance, allowing for more targeted and effective treatment strategies.Furthermore, a funnel plot was generated to assess publication bias.If the funnel plot showed asymmetry or if there was a lack of data points in certain areas, it indicated the presence of bias in the publication of the included studies.

Literature search and screening results
A total of 181 articles were initially detected, 82 articles were read in full, and 52 articles were finally included, all of which were published in Chinese, and the publication years were from 1996 to 2020.The literature screening process is shown in Figure 1.

Inclusion studies and basic characteristics
52 RCTs involved 3362 participants were included.Among these participants, 1699 were in the treatment group, while 1663 cases in the control group.The smallest sample size in the included studies was 35 cases, whereas the largest was 122 cases.More detailed characteristics are in Table 2.

The risk of bias in included studies
According to the RoB 2.0 criteria, among the 52 included RCTs,8 studies [20,[24][25][26]38,43,46,66] were judged as low risk (15.4%) of bias during randomization, the remaining 44 RCTs did not provide sufficient information on the generation of randomized process (84.6%). All studies ere conducted according to the established intervention allocation, and there were no deviations, which was identified as low risk.All the 52 studies had complete outcome data (100%), and the outcome data were objective.According to the assessment of the bias of outcome measurement, 15.4% of the included literature were at low risk, 84.6% were some concerns, and the bias of selective reporting results was some concerns.Specific risks of bias are shown in Figure 2.
There was no significant heterogeneity between the 3 subgroups (P = .93,I 2 = 0%), so they were merged.The overall result showed that treatment effect of using DDP combined with LNT in the treatment of MPE was higher than that of DDP alone, and the difference between groups was statistically significant (RR = 1.40, 95%CI: 1.33 ~ 1.46, P < .001),which was shown in Figure 3.

Sensitivity analysis in the treatment effects.
Sensitivity analysis results showed that there were no qualitative changes in the indicator, which indicated the treatment effect results remained consistent and stable (Fig. 4).Additionally, publication bias was assessed to determine if there was any bias in the selection and publication of studies.Figure 5 displays the distribution of points on both sides, indicating some asymmetry and partial leaning.This suggests the possibility of publication bias, where studies with positive or significant results are more likely to be published, while those with negative or nonsignificant results may be less likely to be published.

3.4.3.
Life quality evaluation.52,[54][55][56]62,63,65] After analysis, heterogeneity was low (P = .99,I 2 = 0%), and a fixedeffect model was used.The result showed that based on DDP, the use of LNT increased the quality of life.The difference  between groups was statistically significant (RR = 1.45, 95%CI: 1.35 ~ 1.56, P < .001)(Fig. 6).The 27 RCTs were further divided into 3 subgroups according to the doses of cisplatin, which categorized as follows: Doses below 40mg (including 40mg), Doses of 40mg to 60mg (including 60mg), and doses above 60mg.Table 3 provides a tabulated summary of the RR values for each subgroup.The results indicated that the subgroup of doses above 60mg had the highest RR value, doses of 40mg to 60mg had a slightly lower RR value, while the subgroup with doses below 40mg had the lowest.These findings suggested that higher doses of cisplatin may lead to a stronger treatment effect compared to lower doses.

The incidence of liver function injury. 18 RCTs
reported the incidence of liver function injury, 2 of which had a liver injury, [37,57] and the remains were normal.As shown in the Figure 9, a fixed-effect model (P = .54,I 2 = 0%) was conducted.The result showed that the combined use of LNT was not significant in reducing the incidence of liver injury (RR = 0.79, 95%CI: 0.20 ~ 3.15, P = .74).

3.4.7.
The incidence of renal injury.18 RCTs reported the incidence of renal injury, in which none of the participants suffered renal injury.

Discussion
In the studies, a comprehensive meta-analysis of 52 RCTs was conducted, which involved a total of 3, 362 participants.The meta-analysis revealed that the combination of LNT with DDP   resulted in a significantly higher treatment effect for MPE compared to DDP alone.At the same time, the use of LNT was associated with improved quality of life.In terms of ADR, the combined use of LNT could significantly decrease the incidence of gastrointestinal reactions, and relieve the incidence of bone marrow suppression, liver function injury, fever, and chest pain to a certain extent.Overall, the combined use of LNT with DDP showed good efficacy in the treatment of MPE without increasing the ADR incidence.Therefore, LNT is an ideal treatment for MPE, which has high clinical application value.
The anti-tumor and autoimmune functions of LNT have been demonstrated in clinical pharmacology experiments.LNT acts as a biological response modulator, meaning that it does not directly target tumor cells but acts on host mediation. [27]y doing so, LNT can improve and activate the host defense mechanism, assisting in the production of anti-tumor effects.MPE is characterized by the accumulation of fluid in the pleural space due to the presence of tumor cells.By enhancing the host defense mechanism, LNT can potentially inhibit tumor growth and metastasis, leading to a reduction in the accumulation of fluid in the pleural space.This can alleviate symptoms such as dyspnea, chest pain, and coughing, improving the patient quality of life.LNT can stimulate the body T cells, activate macrophages, and play a natural killing role in the body-dependent macrophages and natural killer cell (NK) cytotoxic effect, and finally achieve the purpose of anti-tumor.The combination of LNT and chemotherapy drugs can play a certain synergistic effect, and has a protective and regulatory effect on the immune function of patients after chemotherapy.Activation of the exudate immune cells in the chest and abdomen, and then indirectly kill or inhibit tumor cells. [68]Studies have confirmed that local administration of LNT can promote local chemical reactions and form chemical pleurisy.At the same time, it can also stimulate pleural adhesion and fixation, thicken the pleural cavity, block the pleural cavity, reduce the permeability of tumor blood vessels and hinder the formation of tumor blood vessels, and enhance the interstitial reaction of fibrous hyperplasia in tumor tissue.It can activate the function of immune cells in the thoracic cavity, enhance the induction of tumor-specific killer T cells, enhance the body immunity, and reduce its side effects.
This study has the following innovation points worth highlighting.Firstly, it only included studies in which the generation of the randomized method was scientifically sound which enhanced the reliability and validity of the evidence-based findings for the clinical use of LNT combined with DDP in MPE.Secondly, the research indicators used in this study are  comprehensive.In addition to the analysis of treatment effects and life quality, the study also paid attention to various outcome indicators such as the ADR incidence, including bone marrow suppression, gastrointestinal reactions, liver function injury, renal injury, fever, and chest pain.By considering multiple outcome measures, the study provided a more holistic understanding of the impact of LNT combined with DDP in the treatment of MPE.Conversely, there were some limitations in the study: the included studies were all Chinese articles, which may be the geographical limitations of LNT in clinical use.According to the trend of point distribution in the publication bias chart, there is publication bias in this study.Studies with smaller sample sizes were more likely to show a better effect of the trial group, and the RR value of the study result was larger.It probably stems from the selective reporting of clinical study results.From a practical perspective, more positive results are more likely to be published, and the negative results are relatively difficult to obtain.Therefore, we suggest that clinical researchers develop more rigorous and scientific clinical research protocols, conduct multi-center, largesample double-blind experiments, and produce more convincing research results.

Conclusion
In summary, the study uses the meta-analysis method to comprehensively analyze and evaluate the efficacy and safety of LNT combining DDP in the treatment of MPE, to provide a new evidence-based medical basis for the rational use of MPE patients.If the future appears more large-sample, multi-center, prospective, randomized, double-blind studies, the certainty of the evidence will be higher.

Figure 1 .
Figure 1.Flow chart of literature screening.

Figure 2 .
Figure 2. Summary of the risk of bias assessment of the included RCTs.RCTs = randomized controlled trials.

Figure 3 .
Figure 3. Forest plot of the treatment effect LNT in the treatment of MPE.LNT = lentinan for injection, MPE = malignant pleural effusions.

Figure 4 .
Figure 4. Distribution of sensitivity to the treatment effect of LNT in the treatment of MPE.LNT = lentinan for injection, MPE = malignant pleural effusions.

Figure 5 .
Figure 5. Funnel plot of the treatment effect of LNT in the treatment of MPE.LNT = lentinan for injection, MPE = malignant pleural effusions.

Figure 6 .
Figure 6.Forest plot of life quality evaluation in MPE treated with LNT.LNT = lentinan for injection, MPE = malignant pleural effusions.

Figure 7 .Figure 8 .
Figure 7. Forest plot of the incidence of bone marrow suppression in MPE treated with LNT.LNT = lentinan for injection, MPE = malignant pleural effusions.

Figure 9 .Figure 10 .
Figure 9. Forest plot of the incidence of liver function injury in MPE treated with LNT.LNT = lentinan for injection, MPE = malignant pleural effusions.

Table 1
Content table of efficacy evaluation criteria.

Table 2
Characteristics of included literature characteristics.

Table 3
Results for life quality evaluation subgroup analysis of LNT in the treatment of MPE.= mean difference, MPE = malignant pleural effusions, RCTs = randomized controlled trials.www.md-journal.com MD